Abstract

Genomic imprinting results in expression of some autosomal genes from one parental allele only. Human chromosome 11p15, and the syntenic region on mouse distal chromosome 7, contain several imprinted genes, including p57KIP2(CDKN1C) and IGF2. These two genes, which are separated by >700 kb, are both implicated in the pathogenesis of Beckwith-Wiedemann syndrome. We have shown previously that an Igf2/H19 transgene is expressed appropriately and can imprint at ectopic chromosomal locations. To investigate the p57KIP2 region, we similarly tested the imprinting and function of a 38 kb human genomic fragment containing the p57KIP2 gene in transgenic mice. This transgene showed appropriate tissue-specific expression and transgene copy number-dependent expression at ectopic sites. However, the levels of expression are reminiscent of that found for the paternal allele in humans (10%). There was no change in expression levels when the transgene was inherited from the maternal germline. These results suggest that the cis-elements required for enhanced expression of the maternally inherited p57KIP2 allele lie at a distance from the gene. This finding has important implications for the role of this gene in the human disease, in particular with respect to the translocation breakpoints identified in some patients.